In respect to the fact that a large number of bacteria strains are developing resistance to previously life-saving antibiotics, researchers at TUM, the Technische Universitaet Muenchen, have shed light on a metabolic step that is seen in many aggressive microorganisms - such as malaria and tuberculosis pathogens. It is now believed that this finding may provide a new dimensional approach when it comes to a promising target for a new class of antibitoics.
The results were presented in the chemistry journal, Angewandte Chemie.
Research into the bacterial synthesis of isoprene building blocks was started by Professor Adelbert Bacher in collaboration with Drs. Wolfgang Eisenreich and Felix Rohdich in Organic Chemistry and Biochemistry. The involved team was also successful in discovering most of the reaction steps concerned with the new metabolic pathway.
From News-Medical.Net:
The cells of virtually all life forms synthesize essential natural substances belonging to the class of terpenes and steroids from the small isoprene building blocks dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). Mammals and a large number of other organisms generate these essential metabolites via the so-called mevalonate pathway. But most human pathogens, including Plasmodium falciparum, have developed an alternate mechanism for producing these important substances. Now, this special pathway may spell doom for those bacteria. The TUM researchers have unraveled the structural basis of the terminal step in bacterial isoprene synthesis. The crucial enzyme has a most unusual structure, similar to a three-leaf clover, and may open a potent line of attack for custom-tailored antibiotics.
Research into the bacterial synthesis of isoprene building blocks was initiated as early as 12 years ago by Professor Adelbert Bacher in collaboration with Drs. Wolfgang Eisenreich and Felix Rohdich in Organic Chemistry and Biochemistry. Over the years, the team discovered most of the reaction steps of the new metabolic pathway. Yet the structure of the terminal step catalyzed by the IspH enzyme remained stubbornly elusive. Earlier measurements suggested that the active core must be an iron-sulfur cluster with three iron and four sulfur atoms. But other researchers questioned the results, and for many years the crystal structure of the enzyme that would provide the proof could not be determined.
The research team of Professor Groll, Dr. Eppinger, and Dr. Gräwert was able to successfully instrument the process of cracking down the closed-state X-ray structure to reveal the precise folding pattern of the chemical environment of the active site cavity and the protein chain.
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